Acute and chronic inhalation of toxicants, such as airborne particulate material and various organic xenobiotics, can damage respiratory tissues. We have recently discovered that capsaicin, in the form of aerosolized self-defense weaponry, caused inflammation and respiratory epithelial cell damage. The precise mechanism(s), by which capsaicin caused epithelial cell damage, has not been established. The hypothesis of this application is: the expression and activity of vanilIoid receptors (VR1, VR.5 'sv, VRL-1, and VRL-2) by human lung bronchiolar epithelial cells dictates cellular susceptibility to cytotoxicity by capsaicin and other respiratory toxicants. The long-term goal of this research is to provide vital insight into the role of VR1 and other vanilloid receptors in mediating airway epithelial cell damage by various respiratory toxicants, including capsaicin and airborne particulates. The specific goals of this new application are: 1) to establish the potency and mechanism(s) of cell death (i.e., apoptosis or necrosis) for a variety of vanilloid receptor ligands and other vanilloid receptor agonists; 2) to determine the effects of altered levels of VR1 expression on cellular susceptibility to cytotoxicity; 3) to assess the structure function relationships for specific VR1 amino acid residues and N-terminal sequences on the ability of VR1 to mediate cytotoxicity; and 4) To determine the contribution of VR.5'sv, VRL-2, and/or newly discovered Vanilloid Receptor-Like proteins to lung cell susceptibility to respiratory toxicants. These aims will provide: 1) vital insight concerning key mediators of cytotoxic responses in respiratory epithelial cells exposed to toxicants; 2) detailed mechanisms of toxicity of specific respiratory irritants/toxins with the ability to extrapolate these mechanisms to other respiratory toxicants; 3) specific biochemical targets that can be manipulated to ameliorate a variety of respiratory disorders and diseases; and 4) insight into endogenous regulatory mechanisms that influence cellular susceptibility to airway toxicants. Outcomes of these investigations can be utilized to predict human responses to respiratory irritants in self-defense weaponry and define the functions of vanilloid receptors lung epithelial cells.